Nav: Home

Gasdermin E: A new approach to cancer immunotherapy that could have broad reach

March 11, 2020

Tumors have figured out various ways to prevent the immune system from attacking them. Medicine, for its part, has fought back with cancer immunotherapies. The major approach uses checkpoint inhibitors, drugs that help the immune system recognize cancer cells as foreign. Another method, CAR T-cell therapy, directly engineers peoples' T cells to efficiently recognize cancer cells and kill them.

But not all patients benefit from these approaches, which work for just a minority of cancer types, and CAR T-cell therapy carries significant risks. New research from Boston Children's Hospital, published March 11 in Nature, adds another strategy to the arsenal, one that could potentially work in more types of cancer. It reactivates a gene called gasdermin E, harnessing an immune response we already have but that is suppressed in many types of cancer.

"Gasdermin E is a very potent tumor suppressor gene, but in most tumor tissues, it's either not expressed or it's mutated," says Judy Lieberman, MD, PhD, of the Program in Cellular and Molecular Medicine (PCMM), the study's principal investigator. "When you reactivate gasdermin E in a tumor, it can convert an immunologically 'cold' tumor -- not recognized by the immune system -- into a 'hot' tumor that the immune system can control."

In the study, Lieberman and colleagues showed that 20 of 22 cancer-associated mutations they tested led to reduced gasdermin E function. When they re-introduced gasdermin E in a mouse model, they were able to trigger pyroptosis and suppress growth of variety of tumors (triple-negative breast tumors, colorectal tumors, and melanoma).

Heating up the immune response

The team also showed, in mouse tumor cell lines, how gasdermin E works. Normally, when cells die, including most cancerous cells, it's through a process called apoptosis, a quiet, orderly death. But if gasdermin E is present and working, cancer cells go down in flames, through a highly inflammatory form of cell death called pyroptosis.

As Lieberman's team showed in live mice, pyroptosis sounds a potent immune alarm that recruits killer T cells to suppress the tumor. The team is now investigating therapeutic strategies for inducing gasdermin E to rally that anti-tumor immune response.

"What we're suggesting is that if we can turn on the danger signal, which is inflammation, we can activate lymphocytes more fully than with other immunotherapy approaches, and have immunity that is potentially much broader," says Lieberman. "Combining activation of inflammation in the tumor with approved checkpoint inhibitor drugs could work better than either strategy on its own."
-end-
Companies interested in collaborating with the scientists to further the research in this area should contact the Boston Children's Technology and Innovation Development Office at TIDO@childrens.harvard.edu.

Zhibin Zhang, PhD, and Ying Zhang, PhD in the Lieberman lab were co-first authors on the paper in Nature. and Hao Wu, PhD, of PCMM was a collaborator. The study was supported by the NIH Tetramer Core Facility, NIH R01 AI139914, a Charles A. King Trust Fellowship, and a Department of Defense Breast Cancer Breakthrough Fellowship Award.

About Boston Children's Hospital

Boston Children's Hospital is ranked the #1 children's hospital in the nation by U.S. News & World Report and is the primary pediatric teaching affiliate of Harvard Medical School. Home to the world's largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 8 members of the National Academy of Sciences, 21 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Discoveries blog and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.

Boston Children's Hospital

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.